Remdesivir-Induced Liver Injury in a Patient With Coronavirus Disease 2019 and History of Congestive Hepatopathy

Remdesivir is an antiviral agent used as supportive care in adults with SARS-COV2-induced pneumonia. We report a case of an 81-year-old patient who developed hepatocellular acute liver injury 48 hours after initiating remdesivir. During the investigation, other causes of hepatotoxicity were excluded. A decrease in transaminases and international normalized ratio (INR) was observed 24 hours after cessation of remdesivir. An abdominal CT demonstrated hepatic congestion, retrograde hepatic venous opacification shortly after intravenous contrast injection, and dilatation of hepatic veins and inferior vena cava. We suggest congestive hepatopathy secondary to remdesivir as a possible component of liver injury.


Introduction
The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CΟV2) infections has led to more than 629 million confirmed cases and over 6.5 million deaths worldwide as of November 2022 [1]. Apart from the pulmonary involvement, direct SARS-COV2-induced liver damage has also been reported [2,3].
No known effective treatment for COVID-19 has been established. Supportive care remains the mainstay and numerous candidate agents have been proposed. Remdesivir, an antiviral agent, was superior to placebo in shortening recovery time in adults hospitalized with respiratory tract infection with Covid-19 [4]. On May 1st, 2020, the US Food and Drug Administration issued an emergency use authorization of remdesivir for the treatment of COVID-19.
We report a case of a patient with COVID-19 who developed hepatotoxicity following remdesivir therapy, in Thessaloniki, Greece in 2021.

Case Presentation
An 81 years old man was admitted with a 2-days history of fever, dyspnea, and hypoxia. He has had a past medical history of hypertension, dyslipidemia, chronic obstructive pulmonary disease (COPD) with emphysema, benign prostatic hyperplasia, and depression. His medication included lisinopril, tamsulosin, duloxetine, simvastatin, and inhaled beclomethasone/formoterol. He had been an ex-smoker while intake of illicit drugs or alcohol was not reported.
On examination, he was alert and orientated, had mild diffuse fine crackles without wheezing, and mild pedal oedema while cardiac auscultation did not reveal definite murmurs. His electrocardiogram demonstrated new-onset atrial fibrillation. Chest X-ray depicted bilateral peripheral opacities. A diagnosis of COVID-19 was confirmed by a positive SARS-COV2 polymerase chain reaction (PCR) test of a nasopharynx specimen.
He started an intravenous 5-day remdesivir course (loading dose of 200mg followed by 100mg once a day), oral dexamethasone 6mg per day, and intravenous empirical antibiotic treatment of lower respiratory superinfection with ampicillin/sulbactam. Regarding his new-onset atrial fibrillation, he was started on anticoagulation with subcutaneous enoxaparin 6.000iu twice a day for stroke prevention and metoprolol for rate control resulting soon in sinus rhythm restoration. He received oxygen therapy with a nasal cannula 1 2 1 1 delivering 6lt per minute. He had a steady improvement and remained ambulatory with decreasing oxygen demands.
Forty-eight hours later, an acute derangement in liver function tests was noticed characterized by a predominant hepatocellular liver injury pattern (alanine aminotransferase/ALT increased from 61 to 1018, aspartate aminotransferase/AST from 65 to 834) ( Figure 1) as well as coagulopathy (INR from 0.9 to 1.8).
Cholestatic liver enzymes demonstrated mild elevation (alkaline phosphatase from 50 to 96U/L, γglutamyltransferase from 28 to 224U/L, total bilirubin 0,9μmol/L). A steady decline of the transaminases and INR was observed 24 hours after the discontinuation of remdesivir, with the levels returning back 9 days later. He remained throughout in good clinical condition, ambulatory, without any alteration regarding his level of consciousness.
His clinical course was complicated by nonsevere Clostridium Difficile infection which was treated successfully with oral Metronidazole and Vancomycin. He was discharged on day eleven, able to restart his normal daily activities without the need for home oxygen support.

Discussion
According to the EASL acute liver injury is defined as the condition in which patients, without underlying chronic liver disease, develop an acute abnormality of liver blood tests, and coagulopathy, but do not have any alteration to their level of consciousness [5]. In this case, the biochemical pattern of injury is hepatocellular (R=ALT/ALP≥5).
Drugs and toxins remain the main etiology of hepatocellular liver injury. Apart from drugs, the hepatocellular pattern of liver injury can be caused by viral, autoimmune, alcoholic and hypoxic hepatitis. Given the history of the patient, the use of alcohol was 2 units per week. In addition, the vital sign chart did not reveal any episode of hypotension or respiratory deterioration, ruling out hypoxic hepatitis [6]. The viral hepatitis panel was negative, too. Autoimmune etiology of liver enzymes elevation has been excluded.
COVID-19 has been linked to elevated liver enzymes [7]. Liver injury has also been found to be more common in severe COVID-19 than in non-severe COVID-19 patients [8]. Elevated aminotransferase levels were indeed more frequent in Intensive Care Unit inpatients as well as patients requiring ventilation [9]. Between the onset of COVID-19 symptoms and sudden ALT peak, there is a gap of 5 days, while liver enzymes were elevated only after forty-eight hours of remdesivir use. The known in vitro toxicity of remdesivir, the time relation, and automatic resolution after discontinuation of the drug, are all aspects demonstrating a causal relation between elevated liver enzymes and remdesivir. Meanwhile, no other drug of his treatment can be related to hepatotoxicity.
In this case, a rise of more than ten times the upper normal limit of AST and ALT, and coagulopathy with INR≥1,5 is observed. Using the US drug-induced liver injury network [5], the patient is classified as having moderate severity liver injury [ Table 1] [5]. Goldman et al, and Wang et al, report a 1-2 ALT and AST elevation as the most common pattern in patients receiving remdesivir, demonstrating that in most cases elevated levels of liver enzymes do not progress to liver injury [10,11]. On the other hand, Leegwater et al [12], presented a case of the potential interaction of remdesivir with P-glycoprotein inhibitors leading to acute liver failure (ALF). While, Carothers et al [13], presented two cases with two possible factors each provoking the ALF, amiodarone with remdesivir in the first case and hypoxic hepatitis with remdesivir in the second case.

Category Severity Description
US Drug-Induced Liver Injury Network  During the workup, Computed Tomography demonstrated inferior vena cava and hepatic vein dilatation, accompanied by slight enlargement of the liver and retrograde hepatic venous opacification of intravenous contrast material injection. All of the above are imaging findings of congestive hepatopathy [14]. The prevalence of liver congestion is high among patients with severe heart failure. Mitral stenosis, tricuspid regurgitation, constrictive pericarditis and cor pulmonale are the most frequent causes of chronic heart failure provoking liver congestion. Taking into consideration the clinical signs of bilateral mild pedal edema, the need for diuretic treatment, and cardiac chamber enlargement depicted in CT, heart failure seems a possible underlying condition. Unfortunately, during his hospitalization echocardiography was not possible. One week after the patient's discharge echocardiography depicted severe systolic dysfunction (left ventricle ejection fraction=45%) [ Figure 4].

FIGURE 4: Echocardiography one week after discharge, demonstrating systolic dysfunction. Left ventricular ejection function 45%.
Thus, undiagnosed pre-existing heart failure was possibly the etiology of congestive hepatopathy. Congestion and hypoperfusion of the liver result in impaired oxygen diffusion and hepatocyte atrophy leading to impaired metabolism of the liver [15,16]. Chronic decrease in liver blood inflow and outflow results in chronic liver hypoxia. Due to a lack of hepatic venous valves, elevated venous pressure in congestive heart failure is transmitted to the sinusoidal bed. Sinusoids are small endothelium-lined capillaries, around small hepatic veins, with open pores increasing the permeability of the liver. Thus, sinusoidal congestion and peri-sinusoidal edema are caused by elevated venous pressure leading to decreased oxygen diffusion, atrophy of the hepatocytes, and impaired hepatocyte metabolism.

Conclusions
As we mentioned, remdesivir is not able to provoke liver injury per se but only mild elevation of liver enzymes. Since recently, only a few cases of remdesivir-induced liver injury have been reported and all of them were linked to either a combination with another drug or hypoxic hepatitis. We propose a possible synergistic act of remdesivir along with congestive hepatopathy as the etiology of acute liver injury in this patient.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.